Pyrazole derivatives and diabetic medicine containing them

ABSTRACT

The present invention provides pyrazole-O-glycoside derivatives represented by the following formulae, used as a diabetic medicine.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to new pyrazole derivatives anddiabetic medicine which have those compounds as an active ingredient.

[0002] Na⁺-dependent glucose transporter (SGLT) is a membrane proteinwhich transports glucose, and SGLT-1 and SGLT-2 are known. SGLT-2 mainlyexpresses in renal uriniferous tubules. Glucose that is filtered inglomeruli is reabsorbed at the renal uriferous tubules via SGLT, and theglucose taken is reused in the body through the bloodstream. When SGLTis inhibited, the amount of the glucose reabsorbed at renal uriniferoustubules lowers, and the glucose is discharged through urine. As aresult, it is considered that the level of blood sugar decreases. At thepresent time, no medicine is clinically used such as that inhibitingreabsorption of glucose in the kidney.

DISCLOSURE OF THE INVENTION

[0003] The object of the present invention is to provide new pyrazolederivatives.

[0004] The object of the present invention is also to provide apharmaceutical composition containing the new compounds.

[0005] The object of the present invention is also to provide apharmaceutical composition for the treatment of diabetes which comprisesthe new compound.

[0006] The object of the present invention is to find and providediabetic-medicine which is easy to synthesize, less toxic and has highercurative effect.

[0007] The present invention also intends to provide urinary sugarexcretion inducers which have the new compounds.

[0008] Further, the present invention intends to provide the use of thenew compounds for producing a pharmaceutical composition which reducesrenal glucose reabsorption at renal uriniferous tubules.

[0009] The inventors have synthesized various derivatives (1A) or (1B)wherein glucose (namely, β-D-glucopyranose) or glucuronic acid (namely,β-D-glucopyranoside uronic acid) is bonded to pyrazole, and vigorouslyinvestigated the action of those derivatives on urinary sugar excretion.As the result of animal tests, they have found that the compounds ofgeneral formula (1A) or (1B) have the outstanding action on urinarysugar excretion and completed the present invention. These compoundshave not ever been synthesized and, therefore, are completely newpyrazole-O-glycoside derivatives and pyrazole-O-glucuronide derivatives.

[0010] Namely, the present invention provides pyrazole derivatives ofthe following general formula (1A) or (1B) or pharmaceuticallyacceptable salts thereof:

[0011] wherein X represents a β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated or β-D-glucuronyl group, of whichone or more hydroxyl groups may be acylated and carboxyl group may beesterified; Y represents a lower alkyl group or perfluoro lower alkylgroup; Z represents a hydrogen atom, lower alkyl group, perfluoro loweralkyl group, aralkyl group or phenyl group; R1 to R5 may be the same ordifferent and represent a hydrogen atom, lower alkyl group, perfluorolower alkyl group, lower alkoxy group, perfluoro lower alkoxy group,lower alkylthio group, perfluoro lower alkylthio group, lower alkylamino group, halogeno group, lower alkanoyl group, lower alkenyl groupor lower alkynyl group, and n represents an integer from 0 to 3.

[0012] The present invention provides a pharmaceutical composition whichcomprises the above-mentioned pyrazole derivatives or pharmaceuticallyacceptable salts thereof as an active ingredient.

[0013] The present invention also provides a pharmaceutical compositionfor the treatment of diabetes which comprises the above-mentionedpyrazole derivatives or pharmaceutically acceptable salts thereof as anactive ingredient.

[0014] The present invention also provides urinary sugar excretioninducers which comprise the above-mentioned pyrazole derivatives orpharmaceutically acceptable salts thereof as an active ingredient.

[0015] Further, the present invention provides the use of theabove-mentioned pyrazole derivatives or pharmaceutically acceptablesalts thereof for producing a pharmaceutical composition which reducesrenal glucose reabsorption at renal uriniferons tobules.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The term “lower” in the present specification indicates 1 to 6carbon atoms, preferably 1 to 4 carbon atoms. The terms “alkyl”,“alkenyl” and “alkynyl” in alkyl group, perfluoro lower alkyl group,lower alkoxy group, perfluoro lower alkoxy group, lower alkylthio group,perfluoro lower alkylthio group, lower alkyl amino group, lower alkanoylgroup, lower alkenyl group or lower alkynyl group may be linear orbranched.

[0017] An alkyl part in “aralkyl group” in the present specification isa lower alkyl group. An aryl part in “aralkyl group” is a monocyclic orbicyclic aromatic substituent having 5 to 12 carbon atoms.

[0018] Examples of the alkyl group include methyl group, ethyl group,propyl group, butyl group, pentyl group, isopropyl group, isobutyl groupand isopentyl group. The perfluoro lower alkyl group is, for example, atrifluoromethyl group. Examples of the lower alkoxy group are methoxygroup, ethoxy group, propyloxy group and isopropyloxy group. Theperfluoro lower alkoxy group is, for example, a trifluoromethoxy group.The lower alkylthio group includes such as methylthio group, ethylthiogroup and propylthio group. The perfluoro lower alkylthio group is, forexample, trifluoromethylthio group. The lower alkyl amino group includessuch as methyl amino group, ethyl amino group, propyl amino group,dimethyl amino group and diethyl amino group. The lower alkanoyl groupis, for example, acetyl group and propionyl group. The lower alkenylgroup includes such as vinyl group, propenyl group and2-methyl-1-propenyl group. The lower alkynyl group is, for example,ethynyl group and propynyl group. The aralkyl group includes such asbenzyl group, benzyl group of which a benzene ring may have one or moresubstituents, phenethyl group and phenethyl group of which a benzenering may have one or more substituents. The substituents of benzyl groupand phenethyl group herein include lower alkoxy group, lower alkylgroup, halogeno group and halogeno lower alkyl group. Examples of thehalogeno group are fluorine atom, bromine atom, chlorine atom and iodineatom.

[0019] The groups for acylating hydroxyl group include acyl group andcarbamate group; acyl group includes such as acetyl group, propionylgroup, benzoyl group and pivaloyl group; carbamate group includes suchas methyl carbonate group, ethyl carbonate group, propyl carbonategroup, isopropyl carbonate group and phenyl carbonate group. The groupsfor esterifying carboxyl group include lower alkyl group such as methylgroup, ethyl group, propyl group and isopropyl group

[0020] In the above-mentioned general formula (1A) or (1B), one or morehydroxyl groups of β-D-glucopyranosyl group which is a group representedby X may be acylated. Especially, one or more hydroxyl groups of thesaid group may be acylated with the groups selected from alkanoyl groupshaving 2 to 20 carbon atoms, lower alkoxycarbonyl groups and benzoylgroup. Examples of such groups are 6-O-acetyl-β-D-glucopyranosyl groupand 6-O-methoxycarbonyl-β-D-glucopyranosyl group.

[0021] Further, one or more hydroxyl groups of β-D-glucuronyl groupwhich is a group represented by X may be acylated and its carboxyl groupmay be esterified. Especially, one or more hydroxyl groups of the saidgroup may be acylated with the groups selected from alkanoyl groupshaving 2 to 20 carbon atoms, lower alkoxycarbonyl groups and benzoylgroup and its carboxylic acid may be esterified with lower alkyl group.An example of such groups is 6-O-methyl-β-D-glucuronyl group.

[0022] The groups represented by X are preferably β-D-glucopyranosylgroup, 6-O-acetyl-acetyl-β-D-glucopyranosyl group,6-O-methoxycarbonyl-β-D-glucopyranosyl group, β-D-glucuronyl group and6-O-methyl-β-D-glucuronyl group. Among them, β-D-glucopyranosyl groupand, β-D-glucuronyl group are more preferable. Particularly, the grouprepresented by X is preferably β-D-glucopyranosyl group of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl groups having 2 to 20 carbon atoms, lower alkoxycarbonyl groupsand benzoyl group. It is more preferable that the group is acylated withalkanoyl group having 2 to 6 carbon atoms or lower alkoxycarbonyl group.Among them, one hydroxyl group is preferably acylated. Most preferably,the hydroxyl group connected to a carbon atom at the 6th position isacylated. Examples of such groups represented by X are6-O-acetyl-β-D-glucopyranosyl group and6-O-methoxycarbonyl-β-D-glucopyranosyl group.

[0023] The groups represented by Y are preferably lower alkyl grouphaving 1 to 3 carbon atoms or perfluoro lower alkyl group having 1 to 6carbon atoms. A methyl group and trifluoromethyl group are particularlypreferable.

[0024] The groups represented by Z are preferably hydrogen atom andlower alkyl group having 1 to 6 carbon atoms. A hydrogen atom, loweralkyl group having 1 to 3 carbon atoms, unsubstituted aralkyl group oraralkyl group of which an aryl part at the 4th position is substitutedand unsubstituted phenyl group are also preferable. Further, hydrogenatom, methyl group, ethyl group, propyl group, isopropyl group,unsubstituted benzyl group or benzyl group of which an aryl part at the4th position is substituted and unsubstituted phenyl group are morepreferable. Among them, hydrogen atom, methyl group, ethyl group, propylgroup and isopropyl group are more preferable, and isopropyl group isparticularly preferable.

[0025] The groups represented by R1 to R5 are preferably lower alkylgroup having 1 to 6 carbon atoms, lower alkylthio group having 1 to 6carbon atoms, halogeno atom, lower alkoxy group, lower alkenyl group andlower alkynyl group. A methyl group, ethyl group, methylthio group,ethylthio group, fluorine atom, methoxy group, vinyl group, propenylgroup, ethynyl group and propynyl group are more preferable. It isparticularly preferable that one or two groups represented by R1 to R5are one of the above-mentioned preferable groups and the rest of thegroups are hydrogen atom. In this case, at least R3 is preferably one ofthe above-mentioned preferable groups. When two groups in R1 to R5 areone of the above-mentioned preferable groups, they may be the same ordifferent from each other, but they are preferably different from eachother. Further, when R3 is either lower alkyl group, lower alkoxy group,lower alkenyl group or lower alkynyl group, R4 or R5 is preferably afluorine atom. It is preferable that one of R1, R2, R4 and R5 ishalogens group, or R1, R2, R4 and R5 are all hydrogen atom and R3 islower alkyl group, lower alkoxy group, lower alkenyl group or loweralkynyl group. It is also preferable that one of R1, R2, R4 and R5 is afluorine atom and R3 is methyl group, ethyl group, methoxy group, vinylgroup or ethynyl group.

[0026] It is preferable that n represents an integer 1.

[0027] Y in general formula (1A) or (1B) is preferably trifluoromethylgroup.

[0028] Further, it is preferable that in general formula (1A) or (1B), Yis trifluoromethyl group and n is 1.

[0029] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucopyranosyl group, ofwhich one or more hydroxyl groups may be acylated with the groupsselected from alkanoyl group having 2 to carbon atoms, loweralkoxycarbonyl group and benzoyl group.

[0030] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucuronyl group, of whichone or more hydroxyl groups may be acylated with the groups selectedfrom alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonylgroup and benzoyl group and its carboxylic acid may be esterified withalkyl group.

[0031] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucopyranosyl group.

[0032] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-acetyl-β-D-glucopyranosylgroup.

[0033] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-carbomethoxy-β-D-glucopyranosylgroup.

[0034] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is β-D-glucuronyl group.

[0035] It is also preferable that in general formula (1A) or (1B), Y istrifluoromethyl group, n is 1 and X is 6-methyl-β-D-glucuronyl group.

[0036] It is also preferable that in general formula (1A) or (1B), X isβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with the groups selected from alkanoyl group having 2 to 20carbon atoms, lower alkoxycarbonyl group and benzoyl group.

[0037] It is also preferable that in general formula (1A) or (1B), X isβ-D-glucopyranosyl group, of which one or more hydroxyl groups may beacylated with lower alkoxycarbonyl group.

[0038] It is also preferable that in general formula (1A) or (1B), Y islower alkyl group having 1 to 3 carbon atoms or perfluoro lower alkylgroup having 1 to 6 carbon atoms; n is 1; X is β-D-glucopyranosyl group,of which one or more hydroxyl groups may be acylated with the groupsselected from alkanoyl group having 2 to 20 carbon atoms, loweralkoxycarbonyl group and benzoyl group; Z is a hydrogen atom, loweralkyl group having 1 to 3 carbon atoms, unsubstituted aralkyl group oraralkyl group of which an aryl part at the 4th position is substitutedor unsubstituted phenyl group; one of R1, R2, R4 and R5 is a halogenogroup, or R1, R2, R4 and R5 are all hydrogen atom and R3 is a loweralkyl group, lower alkoxy group, halogeno group, lower alkenyl group orlower alkynyl group.

[0039] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkyl groupand R4 or R5 is a fluorine atom.

[0040] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkoxy groupand R4 or R5 is a fluorine atom.

[0041] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkynyl group.

[0042] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is lower alkynyl groupand R4 or R5 is a fluorine atom.

[0043] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkenyl group.

[0044] It is also preferable that in general formula (1A) or (1B), Y isa methyl group; n is 1; X is β-D-glucopyranosyl group, of which one ormore hydroxyl groups may be acylated with the groups selected fromalkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl groupand benzoyl group; Z is an isopropyl group; R3 is a lower alkenyl groupand R4 or R5 is a fluorine atom.

[0045] It is also preferable that in general formula (1A) or (1B), Y isa methyl group or trifluoromethyl group; n is 1; X is β-D-glucopyranosylgroup, of which one or more hydroxyl groups may be acylated with thegroups selected from alkanoyl group having 2 to 20 carbon atoms, loweralkoxycarbonyl group and benzoyl group; Z is a hydrogen atom, isopropylgroup, aralkyl group or phenyl group; one of R1, R2, R4 and R5 is afluorine atom and R3 is a methyl group, ethyl group, methoxy group,vinyl group or ethynyl group.

[0046] The compounds or pharmaceutically acceptable salts thereofdescribed below are also preferable:

[0047]4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0048]4-((4-ethylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0049]4-((4-propylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0050]4-((4-isopropylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0051]4-((4-methylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0052]4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0053]4-((4-propylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0054]4-((4-isopropylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0055]4-((4-vinylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0056]4-((4-ethynylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0057]4-((4-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0058]4-((4-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0059]4-((4-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0060]4-((4-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0061]4-((3-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0062]4-((3-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0063]4-((3-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0064]4-((3-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0065]4′-((4′-methylthiophenyl)methyl)-5′-trifluoromethyl-3′-O-(6-0-carbomethoxy-β-D-glucopyranosyl)-1H-pyrazole;

[0066]4′-((4′-ethylphenyl)methyl)-5′-(trifluoromethyl)-3′-O-(6-0-carbomethoxy-β-D-glucopyranosyl)-1H-pyrazole;

[0067]4′-((4′-methylthiophenyl)methyl)-5′-trifluoromethyl-3′-O-(2,3,4,6-0-tetraacetyl-β-D-glucopyranosyl)-1H-pyrazole;

[0068]4′-((4′-ethylphenyl)methyl)-5′-(trifluoromethyl)-3′-O-(2,3,4,6-0-tetraacetyl-β-D-glucopyranosyl)-1H-pyrazole;

[0069]4-[(4-trifluoromethoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0070]4′-[(4′-trifluoromethoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-0-tetraacetyl)-β-D-glucopyranoside;

[0071]4′-[(4′-trifluoromethoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0072]4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0073]4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;

[0074]4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0075]4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0076] 4′-[(4-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;

[0077] 4′-[(4-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0078]4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0079]4′-[(4-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside;

[0080]4′-[(4-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0081]4′-((3-fluoro-4-methoxyphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0082]4′-((3-fluoro-4-methylphenyl)methyl)-1′-isopropyl-5′-i-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0083]4′-((2-fluoro-4-methoxyphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0084]4′-((2-fluoro-4-methylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0085]4′-((2-fluoro-4-ethylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0086]4′-((3-fluoro-4-ethylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0087]4′-((4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0088]4′-((2-fluoro-4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0089]4′-((3-fluoro-4-ethynylphenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0090]4′-((4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0091]4′-((3-fluoro-4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0092]4′-((2-fluoro-4-(1-propynyl)phenyl)methyl)-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0093]4-((3-fluoro-4-methoxyphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0094]4-((3-fluoro-4-methylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0095]4-((2-fluoro-4-methoxyphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0096]4-((2-fluoro-4-methylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0097]4-((2-fluoro-4-ethylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0098]4-((3-fluoro-4-ethylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0099]4-((4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0100]4-((2-fluoro-4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0101]4-((3-fluoro-4-ethynylphenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0102]4-((4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0103]4-((3-fluoro-4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0104]4-((2-fluoro-4-(1-propynyl)phenyl)methyl)-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0105]4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0106]4-((4-ethylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0107]4-((4-propylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0108]4-((4-isopropylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0109]4-((4-methylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0110]4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0111]4-((4-propylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0112]4-((4-isopropylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0113]4-((4-vinylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0114]4-((4-ethynylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0115]4-((4-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0116]4-((4-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0117]4-((4-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0118] 4-((4-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside uronic acid;

[0119]4-((3-methylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0120]4-((3-ethylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0121]4-((3-propylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0122]4-((3-isopropylthiophenyl)ethyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0123] methyl4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranouronate;and

[0124] ethyl4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranouronate.

[0125] Among the above-mentioned examples, the following compounds orpharmaceutically acceptable salts thereof are particularly preferable:

[0126]4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside;

[0127]4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid;

[0128]4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0129]4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0130]4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0131]4′-[(4-ethylphenyl)methyl]-1′-[(4′-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0132]4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0133]4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0134]4-[(3-fluoro-4methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0135]4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0136]4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside;

[0137]4′-[(2-fluoro-4-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;

[0138]4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-,β-D-glucopyranoside; and

[0139]4′-[(33′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside.

[0140] Among the above-mentioned examples, the following compounds orpharmaceutically acceptable salts thereof are particularly preferable:

[0141] The following compounds or pharmaceutically acceptable saltsthereof are also preferable:

[0142]4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside;and

[0143]4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside.

[0144] As methods for producing pyrazole derivatives (1A) or (1B) in thepresent invention, for example, the compounds are produced in accordancewith methods described below when X is β-D-glucopyranosyl group orβ-D-glucuronyl group.

[0145] For example, the compound shown as the compound (2) of thepresent invention can be obtained by methods described as follows.1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(4) (prepared by methods described in J. Med. Chem. 1996, 39, 3920-3928)is reacted with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in thepresence of potassium carbonate in chloroform-water overnight. Theproduct is purified by using such as the chromatography andtetra-O-acetyl intermediate (6) can be obtained, and then thisintermediate is deprotected in a potassium hydroxide aqueous solution toobtain the intended compound (2).

[0146] For example, the compound shown as the compound (3) of thepresent invention can be obtained by methods described as follows.1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(7) (prepared by methods described in J. Med. Chem. 1996, 39, 3920-3928)and 2,3,4-tri-O-benzyl-D-glucopyranoside uronic acid benzyl ester (8)are reacted with triphenylphosphane and diethyl azodicarboxylate (DEAD)in tetrahydrofuran for 1.5 hours. The product is purified by using suchas the chromatography and tetra-benzyl intermediate (9) can be obtained.Then this intermediate is deprotected under hydrogen atmosphere by 20%Pd(OH)₂ to obtain the intended compound (3).

[0147] For example, the compound shown as the compound (15) of thepresent invention can be obtained by methods described as follows. Ahydroxyl group of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-3H-pyrazole-3-one(7) is protected by tert-butyldimethylsilylchloride to obtain compound(10). Benzyl alcohol is reacted with a nitrogen atom on pyrazole of thecompound in accordance with Mitsunobu reaction to obtain (11). TBS groupis then deprotected by diluted hydrochloric acid and reacted with2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (5) in the presence ofpotassium carbonate in chloroform-water overnight. The product ispurified by using such as the chromatography and tetra-O-acetylintermediate (13) can be obtained. Then this intermediate is deprotectedin a potassium hydroxide aqueous solution to obtain (14). A primaryhydroxyl group of the obtained compound (14) is reacted with methylchlorocarbonate to obtain the intended compound (15).

[0148] For example, the compound shown as the compound (21) of thepresent invention can be obtained by methods described as follows. Ethylacetoacetate and 3-fluoro-4-methoxybenzaldehyde are reacted withtrimethylsilylchloride and sodium iodide in acetonitrile to obtain anintermediate (16) and by forming a ring structure with hydrazine,1,2-dihydro-4-[(3-fluoro-4-methoxylphenyl)methyl]-5-methyl-3H-pyrazole-3-one (17) can be obtained. Then,2,3,4,6-tetrabenzylglucopyranose is reacted with a hydroxyl group onpyrazole thereof in accordance with Mitsunobu reaction to obtain (18)and a nitrogen atom in the 1st position of pyrazole thereof isisopropylated by cesium carbonate and isopropyl iodide to obtaincompound (19). A benzyl-protecting group of (19) is deprotected underhydrogen atmosphere by 20% Pd(OH)₂ to obtain compound (20), and ahydroxyl group at the 6th position of (20) is reacted with methylchlorocarbonate in collidine to obtain the intended compound (21).

[0149] For example, the compound shown as the compound (27) of thepresent invention can be obtained by methods described as follows. Ethylacetoacetate and 3-fluoro-4-methylbenzaldehyde are reacted withtrimethylsilylchloride and sodium iodide in acetonitrile to obtain anintermediate (22) and by forming a ring structure with hydrazine,1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3H-pyrazole-3-one (23) can be obtained. Then,2,3,4,6-O-tetraacetyl-α-D-glucopyranosyl bromide is reacted withhydroxyl group on pyrazole thereof by silver carbonate to obtain (24)and a nitrogen atom at the 1st position of pyrazole thereof isisopropylated by cesium carbonate and isopropyl iodide to obtaincompound (25). An acetyl-protecting group of compound (25) isdeprotected by 1N LiOH to obtain compound (26), and a hydroxyl group atthe 6th position of compound (26) is reacted with methyl chlorocarbonatein collidine to obtain the intended compound (27).

[0150] Pyrazole-0-glycoside derivatives and pyrazole-0-glucuronidederivatives of the present invention produced by the above-mentionedmethods can be easily isolated and purified from the reaction mixture byordinary methods for isolation and purification, such as the extractionby solvents, chromatography and crystallization.

[0151] A hydroxyl group of the compounds of the present invention may besubstituted with appropriate substituents which are exchanged to ahydroxy group in vivo. The substituents of hydroxyl group are, forexample, acyl group and carbamate group. An acyl group includes such asalkanoyl group having 2 to 20 carbon atoms and benzoyl group andcarbamate group includes such as lower alkoxycarbonyl group. Especially,the substituents of hydroxyl group of glucopyranosyl group arepreferably carbamate group which is lower alkoxycarbonyl group and morepreferably methoxycarbonyl group. A carboxyl group of the compounds ofthe present invention may be substituted with appropriate substituentswhich are exchanged to a carboxyl group in vivo. The substituents ofcarboxyl group are, for example, lower alkyl group such as methyl groupand ethyl group.

[0152] When the compounds shown in general formula (1A) or (1B) of thepresent invention can form salts thereof, the salts should bepharmaceutically acceptable. When an acidic group exists in the formula,the salts to the acidic group include such as ammonium salt; salts ofalkali metal like sodium and potassium; salts of alkali earth metal likecalcium and magnesium; aluminum salt; zinc salt; salts of organic aminelike triethylamine, ethanolamine, morpholine, piperidine anddicyclohexylamine and salts of basic amino acid like arginine andlysine. When a basic group exists in the formula, the salts to the basicgroup include such as salts of inorganic acid like hydrochloric acid,sulfuric acid and phosphoric acid; salts of organic carboxylic acidoxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleicacid, fumaric acid, tartaric acid, succinate and glutamic acid and saltsof organic sulfonic acid line methanesulfonic acid and p-toluenesulfonicacid. The salts can be formed by combining the compounds of generalformula (1A) or (1B) and necessary acid or base in the appropriateamount and ratio in a solvent and decomposer. They can be also obtainedby the cation or anion exchange from the form of other salts.

[0153] The compounds of general formula (1A) or (1B) of the presentinvention include solvates such as hydrates and alcohol adducts.

[0154] In the present invention, an inhibitor having the compounds ofgeneral formula (1A) or (1B) or salts thereof as an active ingredientcan be used as pharmaceutical compositions, in particular, for thetreatment of diabetes.

[0155] In the present invention, when the pyrazole-O-glycosidederivatives and pyrazole-O-glucuronide derivatives are used as thepharmaceutical compositions, for example, diabetic medicine, they can begiven by oral or parenteral administration such as intramuscular,hypodermic and intravenous administrations and suppository. Though thedosage given for the above-mentioned purpose is determined depending onthe therapeutic effect, administration method, treatment period, age andweight of the patient, the daily dose for adults is usually 1 μg to 10 gby oral administration and 0.01 μg to 1 g by parenteral administration.

[0156] Further, when pyrazole-O-glycoside derivatives andpyrazole-O-glucuronide derivatives of the present invention are preparedas an oral preparation, they can be prepared by ordinary methods afteradding diluent bases and, if necessary, binders, disintegrants,lubricants, coloring agents and flavoring agents, in the form oftablets, powders, pills, granules, capsules, suppositories, solutions,dragees, depots or syrups. Diluent bases include such as lactose,cornstarch, sucrose, glucose, sorbit and crystalline cellulose; Bindersinclude such as polyvinyl alcohol, polyvinyl ether, ethyl cellulose,methyl cellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropyl cellulose, hydroxypropyl starch and polyvinylpyrrolidone;Disintegrants include such as starch, gelatin powder, crystallinecellulose, calcium carbonate, sodium hydrogen carbonate, calciumcitrate, dextran and pectin; Lubricants include such as magnesiumstearate, talc, polyethylene glycols, silica and hardened vegetable oil;Coloring agents include those whose addition to pharmaceutical compoundsis permitted; Flavoring agents includes such as cocoa powder, menthol,aromatic acid, mentha oil, borneol and cassia powder. Their tablets andgranules may be coated with sugar, gelatin and other coating agents, ifnecessary.

[0157] When injectable solutions are prepared, they can be prepared byordinary methods after adding pH adjuster, buffering agents, stabilizingagents and preserving agents, if necessary, in the form of hypodermic,intramuscular, and intravenous injectable solutions.

EXAMPLES

[0158] The following Examples will further illustrate the presentinvention. They are preferred embodiments of the present invention,which by no means limit the invention.

Example 1

[0159] Synthesis of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside

[0160] Process 1

[0161] Synthesis of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranoside

[0162] 519 mg (1.80 mmol) of1,2-dihydro-4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920-3928),1.258 g (3.06 mmol) of 2,3,4,6-O-tetraacetyl-α-D-glucopyranosyl bromide,112 mg (0.36 mmol) of benzyl tri-n-butylammonium chloride and 1.244 g(9.0 mmol) of potassium carbonate were stirred at room temperature for21 hours after adding 0.1 mL of water and 4 mL of chloroform. After thereaction was completed, the mixture was controlled by 10% hydrochloricacid to show pH7. After adding 5 mL of chloroform and removing waterlayer, organic layer was washed with 4 mL of saturated sodiumbicarbonate aqueous solution and 4 mL of saturated aqueous sodiumchloride solution, respectively. After the product was dried withmagnesium sulfate and concentrated, it was purified by silica gel columnchromatography (chloroform: methanol=20:1 (V/V)) to obtain 870 mg (1.41mmol) of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetraacetyl)-β-D-glucopyranosidein the form of pale yellow oily product.

[0163]¹H-NMR (300 MHz, DMSO-d6) δ: 1.92(3H, s), 2.03(3H, s), 2.05(3H,s), 2.10(3 H, s), 2.45(3H, s), 3.74(2H, s), 4.21(1H, dd, J=2.4, 12.6Hz), 4.28(1H, dd, J=4.2, 12.6 Hz), 5.19-5.28(4H, m), 5.41(1H, d, J=6.3Hz), 7.09(2H, d, J=8.1 Hz), 7.16(2H, d, J=8.1 Hz). ESI-MS(m/z):619[(M+H)⁺], 617[(M−H)⁻]

[0164] Process 2

[0165] Synthesis of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside

[0166] 804mg (1.30 mmol) of4′-((4′-methylthiophenyl)methyl)-5′-(trifluoromethyl)-1H-pyrazole-3′-O-(2,3,4,6-O-tetraacetyl)-1-D-glucopyranosidein the form of pale yellow oil was dissolved in 6 mL of ethanol. 0.8 mLof 50% aqueous solution of potassium hydroxide was added thereto and themixture was stirred at, room temperature for 10 minutes. After thereaction was completed, the mixture was controlled by 10% hydrochloricacid to show pH 7 and further stirred for 24 hours. Crystals thus formedwere taken by filtration and washed with 5 mL of ethanol. Then the oilyproduct obtained by concentrating the washings was purified by silicagel column chromatography (chloroform: methanol=10:1 (V/V)) to obtain321 mg (0.71 mmol) of4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranosidein the form of white crystals.

[0167]¹H-NMR (300 MHz, DMSO-d6) δ: 2.43(3H, s), 3.15-3.25(4H, m),4.39(1H, dd, J=5.3, 12.0 Hz), 3.67(1H, d, J=12.0), 3.75(2H, s), 4.92(1H,br-s), 5.04(1H, br-s), 5.12(1H, br-s), 7.12(2H, d, J=8.7 Hz), 7.16(2H,d, J=8.7 Hz). ESI-MS(m/z): 449[(M−H)^(−])

Example 2

[0168] Synthesis of4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-O-β-D-glucopyranosideUronic Acid

[0169] Process 1

[0170] Synthesis of benzyl4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4-O-tribenzyl-β-D-glucopyranouronate

[0171] 199 mg (0.359 mmol) of 2,3,4-tri-O-benzyl-D-glucopyranosideuronic acid benzyl ester (SIGMA), 99 mg (0.367 mmol) of1,2-dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920-3928) and109 mg (0.416 mmol) of triphenylphosphane were dissolved in 0.5 ml ofdried THF (not containing stabilizer). 0.18 ml (0.40 mmol) of 40%toluene solution of diethyl azodicarboxylate was added thereto undercooling with ice and the mixture was stirred at room temperature for 1.5hours. The reaction mixture was directly purified by silica gelchromatography (hexane˜ethyl acetate: hexane=1:10˜1:5) and concentratedunder reduced pressure to obtain 127 mg (0.1577 mmol) of benzyl4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4-O-tribenzyl-β-D-glucopyranouronatein the form of pale yellow oily product.

[0172]¹H-NMR (300 MHz, DMSO-d6) δ: 1.12 (3H, t, J=7.8 Hz), 2.50 (2H, q,J=7.8Hz), 3.64-3.86 (4H, m), 3.90-4.02 (1H, m), 4.05-4.20 (1H, m),4.40-4.58 (3H, m), 4.65-4.82 (3H, m), 5.10 (1H, d, J=12.1 Hz), 5.15(1H,d, J=12.1 Hz), 5.20-5.30 (1H, br), 6.90-7.35 (24H, m)

[0173] Process 2

[0174] Synthesis of4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-O-β-D-glucopyranosideUronic Acid

[0175] 122 mg (0.151 mmol) of benzyl 4′-[(4′-ethylphenyl)methyl]-5′-(trifluoromethyl)-1H-pyrazole-3′-yl-2,3,4,-O-tribenzyl-β-D-glucopyranouronatewas dissolved in 4 ml of ethyl acetate and 4 ml of methanol and, in thepresence of 204 mg of 20%-palladium hydroxide-carbon (50% wet, Aldrich)under hydrogen atmosphere at normal pressures, stirred at roomtemperature for 8 hours. After filtrating 20%-palladium hydroxide-carbonand washing the mixture with 100 ml of dichloromethane: methanol (4:1),the filtrate was evaporated under reduced pressure. The obtained solidsubstance was suspended in the distilled water and purified by SedPackcolumn (water: methanol=1:0˜0:1). Then the product was evaporated underreduce pressure at 40° C. in the bath or lower to obtain 22 mg (0.050mmol) of4-[(4-ethylphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranosideuronic acid in the form of amorphous white solid substance.

[0176]¹H-NMR (300 MHz, DMSO-d6) δ: 1.19 (3H, t, J=7.5 Hz), 2.58 (2H, q,J=7.5 Hz), 3.35-3.51 (2H, m), 3.52-3.65 (1H, m), 3.70-3.90 (3H, m),5.00-5.20 (1H, br), 7.06 (2H, d, J=8.4 Hz), 7.09 (2H, d, J-8.4 Hz)ESI-MS(m/z) 445[(M−H)⁺ ], 447 [(M+H) ⁺]

Example 3

[0177] Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-β-D-glucopyranoside

[0178] Process 1

[0179] Synthesis of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

[0180] 4.76 g (17.6 mmol) of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3H-pyrazole-3-one(prepared by methods described in J. Med. Chem. 1996, 39, 3920-3928) and1.57 g (23.1 mmol) of imidazole were dissolved in 20 ml ofdimethylformamide. 2.98 g (19.8 mmol) of t-butyldimethylsilylchloridewas added thereto and the mixture was stirred at room temperature for 30minutes. After adding 100 ml of water, the mixture was extracted with amixed solution of ethyl acetate-hexane (2:1) three times. The organiclayer was washed with water, dried over sodium sulfate and concentratedto obtain 6.9 g of the intended product (17.9 mmol, quantitative).

[0181]¹H-NMR(300 MHz, CDCl₃) δ: 0.21 (6H, s), 0.93 (9H, s), 1.19 (3H, t,J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 3.74 (2H, s), 7.09 (4H, pseudo ABq)ESI-MS(m/z) 269 [(M−TBS)⁻]

[0182] Process 2

[0183] Synthesis of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

[0184] 0.39 g (1.0 mmol) of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole,0.30 g (1.1 mmol) of triphenylphosphane and 0.14 ml (1.4 mmol) of benzylalcohol were dissolved in 2.0 ml of anhydrous tetrahydrofuran andstirred at room temperature. 0.50 ml (1.1 mmol) of 40% toluene solutionof diethyl azodicarboxylate was slowly added thereto and, 20 minuteslater, the mixture was concentrated. Then 1 ml of hexane was added, andformed sediments were taken by filtration, concentrated and purified bysilica gel column (hexane→5% ethyl acetate/hexane) to obtain 0.40 g(0.83 mmol) of the intended product (83%).

[0185]¹H-NMR(300 MHz, CDCl₃) δ: 0.22 (6H, s), 0.92 (9H, s), 1.20 (3H, t,J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.74 (2H, s), 5.19 (2H, s), 7.06 (4H,pseudo ABq), 7.11-7.33 (5H, m)

[0186] Process 3

[0187] Synthesis of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole

[0188] 0.40 g (0.83 mmol) of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazolewas dissolved in 2 ml of tetrahydrofuran and 0.5 ml of methanol and 1 mlof 1M-HCl aqueous solution was added thereto and the mixture was stirredat room temperature for 7 hours. After adding 5 ml of water, the mixturewas extracted with 5 ml of ethyl acetate three times. The product wasdried over sodium sulfuric anhydride, concentrated and purified bysilica gel column (hexane→10% ethyl acetate/hexane) to obtain 0.27 g(0.74 mmol) of the intended product (89%).

[0189]¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 2.61 (2H, q,J=7.6 Hz) 3.77 (2H, s), 5.18 (2H, s), 7.07-7.31 (9H, m) ESI-MS(m/z) [361(M+H⁺], [3 59 (M−H)⁻]

[0190] Process 4

[0191] Synthesis of 4′-[(4-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

[0192] 1 mL of water and 10 mL of chloroform were added to 0.22 g (0.62mmol) of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole, 0.39 g(0.94 mmol) of 2,3,4,6-O-tetraacetyl-α-D-glucopyranosyl bromide, 0.055 g(0.18 mmol) of benzyl tri-n-butylammonium chloride, 0.79 g (5.7 mmol) ofpotassium carbonate and the mixture was stirred at room temperatureovernight. About 0.1 g of benzyl tri-n-butylammonium chloride was addedthereto and the mixture was further stirred overnight. The organic layerwas purified by silica gel column chromatography (ethyl acetate:hexane=10:1) to obtain 0.39 of roughly purified substance containing theintended product mainly and the further reaction proceeded.

[0193]¹H-NMR(300MHz, CDCl₃) δ: 1.19 (3H, t, J=7.6 Hz), 1.86 (3H, s),2.015 (3 H, s), 2.019 (3H,s), 2.03 (3H, s), 2.58 (2H, q, J=7.6 Hz), 3.74(2H, s), 3.81 (1 H, ddd, J=9.5, 4.2, 2.3 Hz), 4.08 (1H, dd, J=12.5, 2.3Hz), 4.27 (1H, dd, J=12.5, 2.3 Hz), 4.27 (1H, dd, J=12.5, 4.2 Hz),5.16-5.28 (3H, m), 5.24 (2H, s), 5.58-5.63 (1H, m), 7.05 (4H, s),7.16-7.35 (5H, m) ESI-MS(m/z) [691 (M+H)⁺]

[0194] Process 5

[0195] Synthesis of4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0196] 0.28 g of roughly purified substance of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidewas dissolved in 5 ml of ethanol and 5 ml of 4N NaOH aqueous solutionwas added thereto and the mixture was stirred at room temperature. 1hour later, 50 ml of water was added and the mixture was extracted withethyl acetate five times. Then the product was concentrated and purifiedby silica gel column (dichloromethane→10% methanol/dichloromethane) toobtain 0.11 g (0.21 mmol) of the intended product.

[0197]¹H-NMR(300 MHz, CD3OD) δ: 1.19 (3H, t, J=7.6 Hz), 2.58 (2H, q,J=7.6 H z), 3.34-3.46 (4H, m), 3.68 (1H, dd, J=12.0, 4.7 Hz), 3.81 (1H,dd, J=12.0, 2.1 Hz), 3.83 (2H, s), 5.32 (2H, s), 5.34-5.37 (1H, m), 7.07(4H, s), 7.10-7.12 (2H, m), 7.25-7.33 (3H, m)

Example 4

[0198] Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0199] 0.11 g (0.21 mmol) of 4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-β-D-glucopyranosidewas dissolved in 1.5 ml of pyridine and cooled in the ice bath. 0.020 ml(0.26 mmol) of methyl chlorocarbonate was added thereto and thetemperature of the mixture was raised up to room temperature in 0.5hour. 0.020 ml (0.26 mmol) of methyl chlorocarbonate was further added 2hours later and 19 hours later, then the mixture was stirred at roomtemperature for 6 hours. 5 ml of ethyl acetate, 10 ml of 1M HCl aqueoussolution and 20 ml of water were added thereto and the mixture wasextracted with ethyl acetate. Then the product was dried, concentratedand purified by silica gel column (ethyl acetate) to obtain 0.059 g(0.10 mmol) of the intended product (47%).

[0200]¹H-NMR(300 MHz, CDCl3) δ: 1.18 (3H, t, J=7.6 Hz), 2.57 (2H, q,J=7.6 Hz), 3.48-3.60 (4H, m), 3.70 (3H, s), 3.74 (1H, d, J=15.8 Hz),3.82 (1H, d, J=1 5.8 Hz), 4.34 (2, s), 5.22 (1H, d, J=4.4 Hz), 5.23 (2H,s), 7.07 (4H, s), 7.12 (2H, d, J=6.4 Hz), 7.21-7.32 (3H, m) ESI-MS(m/z)[581(M+H)⁺], [579 (M−H)⁻]

Example 5

[0201] Synthesis of4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0202] Process 1

[0203] Synthesis of 4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

[0204] The intended product was obtained in the same manner as shown inProcess 2 of Example 3, by using 4-methoxy benzyl bromide instead ofbenzyl bromide.

[0205]¹H-NMR(300MHz, CDCl₃) δ: 0.22 (6H, s), 0.93 (9H, s), 1.19 (3H, t,J=7.6 Hz), 2.58 (2H, q, J=0.6 Hz), 3.72 (2H, s), 3.78 (3H, s), 5.14 (2H,s), 6.83 (2H, d, J=8.8 Hz), 7.07 (4H, pseudo ABq), 7.16 (2H, d, J=8.8Hz)

[0206] Process 2

[0207] Synthesis of 4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazole

[0208] The intended product was obtained (82%) from 4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-3-O-t-butyldimethylsilyl-1H-pyrazolein the same manner as shown in Process 3 of Example 3

[0209]¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.5 Hz), 2.60 (2H, q,J=7.5 Hz), 3.77 (5H, s), 5.10 (2H, s), 6.81-6.84 (2H, m), 7.07-7.19 (6H,m) ESI-MS(m/z) [391 (M+H)⁺], [389 (M−H)⁻]

[0210] Process 3

[0211] Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

[0212] The roughly purified product of the intended product was obtainedfrom4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazolein the same manner as shown in Process 4 of Example 3.

[0213]¹H-NMR(300MHz, CDCl₃) δ: 1.19 (3H, t, J=7.6 Hz), 1.86 (3H, s),2.07 (3H, s), 2.11 (6H, s), 2.58 (2H, q, J=7.6 Hz), 3.73 (2H, s),3.75-3.84 (1H, m), 4.24-4.30 (1H, m), 5.16 (2H, s), 5.19-5.28 (3H, m),5.56-5.60 (1H, m), 6.75 (2H, d, J=8.8 Hz), 7.05 (4H, s), 7.15 (2H, d,J=8.8 Hz) ESI-MS(m/z) [721 (M+H)⁺]

[0214] Process 4

[0215] Synthesis of 4-[(4-ethylphenyl) methyl]-1-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0216] The intended product was obtained (91% in 2 steps) from4′-[(4′-ethylphenyl)methyl]-1′-[(4-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 3.

[0217]¹H-NMR(300 MHz, CD3OD) δ: 1.19 (3H, t, J=7.6 Hz), 2.57 (2H, q,J=7.6 H z), 3.36-3.44 (4H, m), 3.66-3.82 (2H, m), 3.76 (3H, s), 3.82(2H, s), 5.24 (2 H, s), 5.33-5.36 (1H, m), 6.86 (2H, d, J=8.5 Hz), 7.07(4H, s), 7.12 (2H, d, J=8.5 Hz) ESI-MS(m/z) [553 (M+H)⁺], [551 (M−H)⁻-]

Example 6

[0218] Synthesis of 4′-[(4′-ethylphenyl) methyl]-1′-[(4′-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0219] 0.18-(0.32 mmol) of4-[(4-ethylphenyl)methyl]-1[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranosidewas dissolved in 2 ml of 2,4,6-collidine and cooled down to −50° C.0.035 ml (0.45 mmol) of methyl chlorocarbonate was added thereto and thetemperature of the mixture was raised up to room temperature in 1 hour.27 hours later, 20 ml of ethyl acetate and 20 ml of 1M HCl aqueoussolution were added thereto and the mixture was extracted with ethylacetate. Then the product was dried, concentrated and purified by silicagel column (hexane-ethyl acetate ) to obtain 0.12 g (0.20 mmol) of theintended product (62%).

[0220]¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 2.26 (1H, d,J=2.3 Hz), 2.61 (2H, q, J=7.6 Hz), 2.69 (1H, s), 2.86 (1H, s), 3.45-3.61(4H, m), 3.73 (1H, d, J=15.2 Hz), 3.80 (3H, s), 3.80 (3H, s), 3.88 (1H,d, J=15.2 Hz), 4.37 (1H, d, J=12.3 Hz), 4.49 (1H, dd, J=12.3, 3.0 Hz),5.19 (2H, s), 5.20 (1H, d, J=7.6 Hz), 6.86 (2H, d, J=8.5 Hz), 7.10 (4H,s), 7.16 (2H, d, J=8.5 Hz)

Example 7

[0221] Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0222] Process 1

[0223] Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole

[0224] 0.079 g (0.21 mmol) of4-[(4-ethylphenyl)methyl]-5-trifluoromethyl-3-O-t-butyldimethylsilyl-1H-pyrazole,0.049 g (0.40 mmol) of phenylboronic acid and 0.057 g (0.32 mmol) ofcopper acetate anhydride were dissolved in 5 ml of drieddichloromethane. 0.15 g of molecular sieves 4A powder and 0.032 ml (0.40mmol) of pyridine were added thereto and the mixture was stirred at roomtemperature overnight. Then the reaction mixture was purified by silicagel column (hexane→hexane: dichloromethane=5:1˜3:1) and the main productwas separated to obtain 0.074 g (0.16 mmol) of the intended product(80%).

[0225]¹H-NMR(300MHz, CDCl₃) δ: 0.27 (6H, s), 0.96 (9H, s), 1.21 (3H, t,J=7.6 Hz), 2.61 (2H, q, J=7.6 Hz), 3.84 (2H, s), 7.11 (2H, J=8.3 Hz),7.18 (2H, J=8.3 Hz), 7.35-7.45 (5H, m) ESI-MS(m/z) [461 M+H)⁺], [459(M−H)^(−])

[0226] Process 2

[0227] Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole

[0228] The intended product was obtained (95%) from 4-[(4-ethylphenyl)methyl]-1-phenyl-5-(trifluoromethyl)-3-O-t-butyldimethylsilyl-1H-pyrazolein the same manner as shown in Process 3 of Example 3.

[0229]¹H-NMR(300 MHz, CDCl₃) δ: 1.22 (3H, t, J=7.6 Hz), 2.62 (2H, q,J=7.6 Hz), 3.81 (2H, s), 7.10 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.1 Hz),7.35-7.50 (5H, m), 10.40-10.80 (1H, br-s) ESI-MS(m/z)

[0230] [347 (M+H)⁺], [345 (M−H)^(−])

Process 3

[0231] Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

[0232] The roughly purified product of the intended product was obtainedfrom 4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole inthe same manner as shown in Process 4 of Example 3.

[0233]¹H-NMR(300 MHz, CDCl₃) δ: 1.21 (3H, t, J=7.6 Hz), 1.90 (3H, s),2.02 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.61 (2H, q, J=7.6 Hz),3.80-3.90 (2H, s and 1 H, m), 4.10-4.30 (2H, m), 5.15-5.36 (3H, m), 5.68(1H, d, J=7.5 Hz), 7.10 (2H, d, J=8.3 Hz), 7.15 (2H, d, J=8.3 Hz),7.38-7.47 (5H, m) ESI-MS(m/z) [677 (M+H)⁺]

[0234] Process 4

[0235] Synthesis of4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0236] The intended product was obtained (84% in 2 steps) from theroughly purified product of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 3.

[0237]¹H-NMR(300 MHz, DMSO-d₆) δ: 1.19 (3H, t, J=7.6 Hz), 2.60 (2H, q,J=7.6 Hz), 3.15-3.35 (4H, m), 3.45-3.55 (1H, m), 3.69 (1H, dd, J=11.4,5.7 Hz), 3.85 (1H, d, J=15.6 Hz), 3.92 (1H, d, J=15.6 Hz), 4.55 (1H, t,J=5.7 Hz), 5.03 (1H, d, J=4.5 Hz), 5.13 (1H, d, J=3.9 Hz), 5.35 (1H, d,J=7.5 Hz), 5.41 (1H, d, J=4.5 Hz), 7.17 (2H, d, J=8.3 Hz), 7.22 (2H, d,J=8.3 Hz), 7.47-7.62 (5H, m)

[0238] ESI-MS(m/z) [509 (M+H)⁺], [507 (M−H)⁻]

Example 8

[0239] Synthesis of4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0240] The intended product was obtained (71%) from4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 4.

[0241]¹H-NMR(300 MHz, CDCl₃) δ: 1.22 (3H, t, J=7.6 Hz), 2.18 (1H, br),2.62 (2H, q, J=7.6 Hz), 2.72 (1H, br), 2.89 (1H, br), 3.45-3.63 (4H, m),3.78 (3H, s), 3.81 (1H, d, J=15.6 Hz), 3.98 (1H, d, J=15.6 Hz), 4.37(1H, dd, 12.0, 1.7 Hz), 4.49 (1H, dd, 12.0, 3.6 Hz), 5.32 (1H, d, J=7.2Hz), 7.14 (2H, d, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz), 7.39-7.47 (5H, m)ESI-MS(m/z) [567 (M+H)+], [565 (M−H)−]

Example 9

[0242] Synthesis of4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0243] Process 1

[0244] Synthesis of ethyl 2-[(3-fluoro-4-methoxy)benzyl]-3-oxobutyrate

[0245] 1.69 g (13.0 mmol) of ethyl acetoacetate and 9.6 g (65 mmol) ofsodium iodide were dissolved in 100 ml of acetonitrile and cooled downto 0° C. 8.2 ml (65 mmol) of trimethylsilylchloride was slowly addedthereto and 10 minutes later, 2.0 g (13.0 mmol) of3-fluoro-4-methoxybenzaldehyde was added in three times. 10 minuteslater, the temperature of the mixture was raised up to room temperatureand the mixture was continuously stirred. 6 hours later, the mixture wasmoved into the 60° C. bath and stirred overnight. After the reactionmixture was cooled down, 250 ml of water, 250 ml of ethyl acetate and 50ml of saturated aqueous sodium chloride solution were added thereto, andethyl acetate layer was extracted. The obtained organic layer was washedwith saturated sodium sulfite aqueous solution and dried over anhydrousmagnesium sulfate. Then the product was concentrated and purified bysilica gel column chromatography (EtOAc-Hex; 1:4) to obtain 2.54 g (9.5mmol) of the intended product (yield 73%).

[0246]¹H-NMR (300 MHz, CDCl₃) δ: 6.82-6.96 (3H, m), 4.12-4.20 (2H, m),3.86 (3H, s), 3.71 (1H, t, J=7.8), 3.08 (2H, d, J=8.1), 2.20 (3H, s),1.23 (3H, t, J=7.2).

[0247] Process 2

[0248] Synthesis of1,2-dihydro-4-[(3-fluoro-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-one

[0249] 2.54 g (9.5 mmol) of ethyl2-[(3-fluoro-4-methoxy)benzyl]-3-oxobutyrate was dissolved in 50 ml oftoluene. 0.72 g (14.2 mmol) of hydrated hydrazine was added thereto andthe mixture was stirred at 100° C. overnight. After the reaction mixturewas cooled down, the formed white solid was filtrated and dried by avacuum pump to obtain 1.86 g (7.9 mmol) of the intended product (yield83%).

[0250]¹H-NMR (300 MHz, DMSO-d6) δ: 7.00 (1H, t, J=8.4), 6.86-6.94 (2H,m), 3.75 (3H, s), 3.46 (2H, s), 1.98 (3H, s). ESI-MS(m/z): 237[(M+H)⁺],235[(M−H)⁻].

[0251] Process 3

[0252] Synthesis of 4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0253] 2.3 g (4.2 mmol) of 2,3,4,6-tetra-0-benzyl-D-glucopyranoside, 1.0g (4.2 mmol) of1,2-dihydro-4-[(3-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-oneand 1.1 g (4.2 mmol) of triphenylphophane were dissolved in 40 ml ofdried THF (not containing stabilizer). 1.9 ml(4.2 mmol) of 40% toluenesolution of diethyl azodicarboxylate was added thereto under coolingwith ice and the mixture was stirred at room temperature overnight.After the reaction mixture was concentrated, the product was directlypurified by silica gel column chromatography (hexane˜ethyl acetate:hexane=2:3) and concentrated under reduced pressure to obtain 2.2 g (2.9mmol) of the intended product (yield 70%).

[0254]¹H-NMR (300 MHz, CDCl₃) δ: 7.10-7.32 (20H, m), 6.78-6.92 (2H, m),6.67 (1H, t, J=8.1), 5.51 (1H, d, J=7.5), 4.46-4.92 (10H, m), 3.60-3.76(6H, m), 3.71 (3H, s), 2.07 (3H, s). ESI-MS(m/z): 759[(M+H)⁺],757[(M−H)⁻].

[0255] Process 4

[0256] Synthesis of 4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0257] 2.2 g (2.9 mmol) of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidewas dissolved in 44 ml of dimethylformamide. 9.6 g (29.5 mmol) of cesiumcarbonate and 2.5 g (14.8 mmol) of isopropyl iodide were added theretoand the mixture was stirred at room temperature overnight.

[0258] 200 ml of water, 50 ml of saturated aqueous sodium chloridesolution and 300 ml of dichloromethane were added and the organic layerwas extracted, dried over anhydrous sodium sulfate and concentrated. Theproduct was purified by silica gel column chromatography (hexane˜ethylacetate: hexane=1:3) and concentrated under reduced pressure to obtain1.7 g (2.2 mmol) of the intended product (yield 74%).

[0259]¹H-NMR (300 MHz, CDCl₃) δ: 7.12-7.32 (20H, m), 6.80-6.92 (2H, m),6.68 (1H, t, J=8.4), 5.47 (1H, d, J=7.2), 4.74-4.94 (5H, m), 4.44-4.64(5H, m), 4.24-4.32 (1H, m), 3.73 (3H, s), 3.60-3.72 (6H, m), 2.06 (3H,s), 1.38 (3H, t, J=7.5). E

[0260] SI-MS(m/z): 801[(M+H)⁺].

[0261] Process 5

[0262] Synthesis of4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0263] 1.7 g (2.2 mmol) of 4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidewas dissolved in 70 ml of ethanol. 1.0 g of 20% palladiumhydroxide—carbon was added thereto and the mixture was stirred for 2hours under hydrogen atmosphere. The reaction mixture was filtrated by afilter cell and the filtrate was concentrated and purified by silica gelchromatography (15% methanol: dichloromethane) and then concentratedunder reduced pressure to obtain 828 mg (1.9 mmol) of the intendedproduct (yield 88%).

[0264]¹H-NMR (300 Mz, DMSO-d6) δ: 6.92-7.04 (3H, m), 5.20 (1H, d,J=4.5), 5.11 (1H, d, J=7.2), 5.02 (1H, d, J=3.6), 4.93 (1H, d, J=4.5),4.41 (1H, t, J=5.7), 4.28-4.40 (1H, m), 3.77 (3H, s), 3.56-3.66 (1H, m),3.42-3.52 (1H, m), 3.08-3.24 (4H, m), 2.07 (3H, s), 1.24-1.30 (3H, m).ESI-MS(m/z): [441(M+H)⁺].

Example 10

[0265] Synthesis of4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0266] 820 mg (1.9 mmol) of4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranosidewas dissolved in 8 ml of collidine and cooled down to 0° C. 10 minuteslater, 0.22 ml of methyl chlorocarbonate was added thereto and themixture was stirred for 7 hours, neutralized with 2N HCl and extractedwith ethyl acetate. Then the organic layer was dried over anhydroussodium sulfate, concentrated and purified by silica gel chromatography(ethyl acetate) and then concentrated under reduced pressure to obtain303 mg (0.61 mmol) of the intended product (yield 33%).

[0267]¹H-NMR (300 MHz, CDCl₃) δ: 6.80-6.92 (3H, m), 5.02 (1H, d, J=8.1),4.40 (2H, s), 4.22-4.34 (1H, m), 3.85 (3H, s), 3.78 (3H, s), 3.44-3.66(6H, m), 2.08 (3H, s),1.38 (6H, d, J=6.6). ESI-MS(m/z): [499(M+H)⁺].

Example 11

[0268] Synthesis of4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0269] Process 1

[0270] Synthesis of ethyl 2-[(2-fluoro-4-methoxy)benzyl]-3-oxobutyrate

[0271] 3.4 g (12.7 mmol) of the intended product was obtained (yield65%) from 3.0 g of 2-fluoro-4-methoxybenzaldehyde in the same manner asshown in Process 1 of Example 9.

[0272]¹H-NMR (300 MHz, CDCl₃) δ: 7.07 (1H, t, J=8.7), 6.40-6.62 (2H, m),4.10-4.20 (2H, m), 3.79 (1H, t, J=7.8), 3.77 (3H, s), 3.04-3.18 (2H, m),2.21 (3H, ), 1.21 s (3H, t, J=7.2).

[0273] Process 2

[0274] Synthesis of1,2-dihydro-4-[(2-fluoro-4-methoxylphenyl)methyl]-5-methyl-3H-pyrazole-3-one

[0275] 2.46 g (10.4 mmol) of the intended product was obtained (yield83%) from 3.4 g of ethyl 2-[(2-fluoro-4-methoxy) benzyl]-3-oxobutyratein the same manner as shown in Process 2 of Example 9.

[0276]¹H-NMR (300 MHz, CDCl₃) δ: 7.02 (1H, t, J=8.7), 6.72 (1H, dd,J=2.4, 12.0), 6.66 (1H, d, J=2.7, 8.4), 3.71 (3H, s), 3.47 (2H, s), 1.99(3H, s) ESI-MS(m/z) 237[(M+H)⁺], 235[(M−H)⁻].

[0277] Process 3

[0278] Synthesis of 4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0279] 2.6 g (3.46 mmol) of the intended product was obtained (yield82%) from 1.0 g (4.2 mmol) of1,2-dihydro-4-[(2-fluoro-4-methoxyphenyl)methyl]-5-methyl-3H-pyrazole-3-onein the same manner as shown in Process 3 of Example 9.

[0280]¹H-NMR (300 Mz, DSO-d6) δ: 7.12-7.32 (20H, m), 6.99 (1H, t,J=9.0), 6.50 (1H, dd, J=2.4, 11.7), 6.42 (1H, dd, J=2.7, 8.4), 5.54 (1H,d, J=7.2), 4.44-4.92 (8H, m), 3.60-3.76 (8H, m), 3.62 (3H, s), 2.09 (3H,s) ESI-MS(m/z): 759[(M+H)⁺], 757[(M−H)⁻].

[0281] Process 4

[0282] Synthesis of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0283] 157 mg (0.19 mmol) of the intended product was obtained (yield70%) from 212 mg (0.28 mmol) of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 4 of Example 9.

[0284]¹H-NMR (300 MHz, CDCl₃) δ: 7.14-7.30 (20H, m), 6.99 (1H, t,J=8.7), 6.49 (1H, dd, J=2.4, 11.7), 6.41 (1H, dd, J=2.4, 8.7), 5.50 (1H,d, J=7.5), 4.74-4.96 (5H, m), 4.46-4.66 (5H, m), 4.22-4.32 (1H, m), 3.64(3H, s), 3.60-3.74 (6H, m), 2.08 (3H, s), 1.37 (6H, t, J=6.6).ESI-MS(m/z): 801[(M+H)⁺].

[0285] Process 5

[0286] Synthesis of 4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0287] 80 mg (0.18 mmol) of the intended product was obtained (yield97%) from 150 mg (0.19 mmol) of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 9.

[0288]¹H-NMR (300 MHz, DMSO-d6) δ: 7.09 (1H, t, J=9.0), 6.73 (1H, dd,J=2.7, 12.3), 6.66 (1H, dd, J=2.7, 8.7), 5.18 (1H, d, J=4.8), 5.11 (1H,d, J=7.5), 5.01 (1H, d, J=4.2), 4.91 (1H, d, J=4.2), 4.42 (1H, t,J=6.0), 4.30-4.38 (1H, m), 3.72 (3H, s), 3.53 (2H, s), 3.42-3.66 (2H,m), 3.06-3.24 (4H, m),2.07 (3H, s), 1.28 (3H, d, J=2.7), 1.26 (3H, d,J=2.7). ESI-MS(m/z): 441[(M+H)⁺], 439[(M+H)⁻].

Example 12

[0289] Synthesis of4′-[(2′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0290] 380 mg (0.76 mmol) of the intended product was obtained (yield31%) from 1.1 g (2.42 mmol) of4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside.

[0291]¹H-NMR (300 MHz, CDCl₃) δ: 7.08 (1H, t, J=8.4), 6.52-6.62 (2H, m),5.02 (1H, d, J=7.8), 4.64 (1H, brs), 4.40 (2H, d, J=2.4), 4.24-4.33 (1H,m), 3.77 (3H, s), 3.75 (3H, s), 3.59 (3H, s), 3.10-3.66 (6H, m), 1.38(3H, s), 1.35 (3H, s)

Example 13

[0292] Synthesis of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0293] Process 1

[0294] Synthesis of ethyl 2-[(3-fluoro-4-methyl)benzyl]-3-oxobutyrate

[0295] 4.5 g (17.9 mmol) of the intended product was obtained (yield82%) from 3.0 g (21.7 mmol) of 3-fluoro-4-methylbenzaldehyde in the samemanner as shown in Process 1 of Example 9.

[0296]¹H-NMR (300 MHz, CDCl₃) δ: 7.06 (1H, t, J=8.1), 6.78-6.88 (2H, m),4.15 (2H, q, J=6.9), 3.73 (1H, t, J=7.8), 3.10 (1H, d, J=7.8), 2.22 (3H,s), 2.19 (3H, s), 1.22 (3H, t, J=6.9).

[0297] Process 2

[0298] Synthesis of1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5methyl-3H-pyrazole-3-one

[0299] 2.3 g (10.5 mmol) of the intended product was obtained (yield93%) from 2.84 g (11.3 mmol) of ethyl2-[(3-fluoro-4-methyl)benzyl]-3-oxobutyrate in the same manner as shownin Process 2 of Example 9.

[0300]¹H-NMR (300 MHz, DMSO-d6) δ: 7.11 (1H, d, J=8.4), 6.81-6.89 (2H,m), 3.49 (2H, s), 2.13 (3H, s), 1.98 (3H, s). ESI-MS(m/z): 221[(M+H)⁺]

[0301] Process 3

[0302] Synthesis of4′-[(3′-fluoro-4′-methylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranoside

[0303] 2.1 g (5.0 mmol) of 2,3,4,6-O-tetraacetyl-α-D-glucopyranosylbromide, 1.1 g (5.0 mmol) of1,2-dihydro-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3H-pyrazole-3-oneand 1.38 g (5 mmol) of silver carbonate were dissolved in 50 ml of driedTHF (not containing stabilizer) and the mixture was stirred under darkat 65° C. overnight. The reaction mixture was filtrated with a filtercell and dichloromethane was added thereto. After washing the mixturewith water, the organic layer was dried over anhydrous sodium sulfate,concentrated and purified by silica gel chromatography (hexane ethylacetate: hexane=1:3) and then concentrated under reduced pressure toobtain 1.1 g (2.0 mmol) of the intended product (yield 40%).

[0304]¹H-NMR (300 MHz, CDCl₃) δ: 7.03 (1H, t, J=7.5), 6.82 (1H, dd,J=1.2, 7.8), 6.74 (1H, dd, J=1.5, 10.8), 5.59 (1H, d, J=8.1), 5.16-5.30(3H, m), 4.31 (1H, dd, J=3.9, 12.3), 4.12 (1H, dd, J=2.1, 12.3),3.82-3.88 (1H, m), 3.63 (1H, d, J=15.9), 3.54 (1H, d, J=15.9), 2.20 (3H,d, J=1.5), 2.11 (3H, s), 2.06 (3H, s), 2.03 (3H, s), 2.02 (3H, s), 1.91(3H, s). ESI-MS(m/z): 551[(M+H)⁺], 549[(M−H)⁻].

[0305] Process 4

[0306] Synthesis of4′-[(3-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,-1,6-tetraacetyl)-β-D-glucopyranoside

[0307] 290 mg (0.53 mmol) of4′-[(3′-fluoro-4′-methylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidewas dissolved in 6 ml of dimethylformaldehyde. 1.7 g (5.2 mmol) ofcesium carbonate and 447 mg (2.6 mmol) of isopropyl iodide were addedthereto and the mixture was stirred at room temperature over night.After adding water, saturated aqueous sodium chloride solution anddichloromethane, the organic layer was extracted by a separating funnel,dried over anhydrous sodium sulfate and concentrated. The product waspurified by silica gel chromatography (hexane˜ethyl acetate: hexane=1:3)and then concentrated under reduced pressure to obtain 165 mg (0.28mmol) of the intended product (yield 53%).

[0308]¹H-NMR (300 MHz, CDCl₃) δ: 7.02 (1H, t, J=7.8), 6.82 (1H, d,J=7.8), 6.74 (1 H, d, J=10.8), 5.79 (1H, d, J=8.1), 5.12-5.34 (3H, m),4.18-4.32 (2H, m), 4.06-4.16 (1H, m), 3.78-3.88 (1H, m), 3.48-3.64 (2H,m), 2.19 (3H, s), 2.07 (3H, s), 2.06 (3H, s), 2.04 (3H, s), 2.02 (3H,s), 1.93 (3H, s). ESI-MS(m/z): 593[M⁺].

[0309] Process 5

[0310] Synthesis of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0311] 56 mg (0.09 mmol) of 4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetraacetyl)-β-D-glucopyranosidewas dissolved in 0.2 ml of methanol and 0.4 ml of tetrahydrofuran. 0.38ml of 1N LiOH was added at 0° C. thereto and the mixture was stirred for1 hour. After adding water and ethyl acetate, the organic layer wasextracted, dried, concentrated and purified by silica gel chromatography(15% methanol: dichloromethane) and then concentrated under reducedpressure to obtain 34 mg (0.08 mmol) of the intended product. (yield85%).

[0312]¹H-NMR (300 MHz, DMSO-d6) δ: 7.11 (1H, t, J=8.4), 5.19 (1H, d,J=4.8), 5.09 (1H, d, J=7.5), 4.99 (1H, d, J=3.9), 4.91 (1H, d, J=4.2),4.41 (1H, t, J=5.7), 4.28-4.38 (1H, m), 3.56 (2H, m), 3.54-3.64 (1H, m),3.40-3.50 (1H, m), 3.06-3.24 (4H, m), 2.13 (3H, s), 2.05 (3H, s), 1.26(3H, d, J=3.0), 1.24 (3H, d, J=3.0 ). ESI-MS(m/z): 425[(M+H)⁺],423[(M−H)⁻].

Example 14

[0313] Synthesis of 4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside

[0314] 283 mg (0.59 mmol) of the intended product was obtained (yield75%) from 334 mg (0.787 mmol) of4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 12.

[0315]¹H-NMR (300 MHz, DMSO-d6) δ: 1.26(3H, d, J=6.3 Hz), 1.28 (3H, d,J=6.3 Hz), 2.07(3H, s), 2.15(3H, s), 3.09-3.41(4H, m), 3.56(2H, s),4.10(1H, dd, J=6.0, 11.4 Hz), 4.29(1H, dd, J=1.8, 11.7 Hz), 4.34(1H, m),5.10(1H, d, J=7.8 Hz), 5.13(1H, d, J=5.1 Hz), 5.24(1H, d, J=5.1 Hz),5.31(1H, d, J=5.1 Hz), 6.89-7.13(3H, m). ESI-MS(m/z):483[M+H]⁺481[(M−H)⁻]

Example 15

[0316] Synthesis of4-[(4-ethylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0317] Process 1

[0318] Synthesis of ethyl 2-(4-ethylbenzyl)-3-oxobutyrate

[0319] 3.9 g (15.7 mmol) of the intended product was obtained (yield70%) from 3.0 g of 4-ethylbenzaldehyde in the same manner as shown inProcess 1 of Example 9.

[0320]¹H-NMR (300 MHz, CDCl₃) δ: 4.15 (2H, q, J=7.2), 3.76 (1H, t,J=7.5), 3.12 (2H, d, J=8.1), 2.60 (2H, q, J=7.8), 2.19 (3H, s), 1.21(6H, t, J=7.2)

[0321] Process 2

[0322] Synthesis of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-methyl-3H-pyrazole-3-one

[0323] 3.1 g (14.3 mmol) of the intended product was obtained (yield91%) from 3.9 g of ethyl 2-(4-ethylbenzyl)-3-oxobutyrate in the samemanner as shown in Process 2 of Example 9.

[0324]¹H-NMR (300 MHz, DMSO-d6) δ: 7.06 (4H, s), 3.49 (2H, s), 2.52 (2H,q, J=7.8), 1.99 (3H, s), 1.33 (3H, t, J=7.5) ESI-MS(m/z): 217[(M+H)⁺],215[(M−H)⁻].

[0325] Process 3

[0326] Synthesis of 4′-[(4-ethylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0327] 2.3 g (3.1 mmol) of the intended product was obtained (yield 62%)from 1.0 g (4.6 mmol) of1,2-dihydro-4-[(4-ethylphenyl)methyl]-5-methyl-3H-pyrazole-3-one in thesame manner as shown in Process 3 of Example 9.

[0328]¹H-NMR (300 MHz, CDCl₃) δ: 7.10-7.34 (20H, m), 7.07 (2H, d,J=8.4), 6.97 (2H, d, J=8.4), 5.23 (1H, d, J=6.9), 4.44-5.00 (8H, m),3.56-3.80 (8H, m), 2.50 (2H, q, J=7.5), 2.08 (3H, s), 1.13 (3H, t,J=7.5): ESI-MS(m/z): 739[(M+H)⁺], 737[(M−H)⁻].

[0329] Process 4

[0330] Synthesis of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranoside

[0331] 1.6 g (2.0 mmol) of the intended product was obtained (yield 79%)from 1.9 g (2.6 mmol) of4′-[(4-ethylphenyl)methyl]-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 4 of Example 9.

[0332]¹H-NMR (300 MHz, CDCl₃) δ: 7.14-7.38 (20H, m), 7.07 (2H, d,J=8.1), 6.97 (2H, d, J=8.1), 5.47 (1H, d, J=7.5), 4.20-5.00 (9H, m),3.60-3.76 (8H, m), 2.52 (2H, q J=7.8), 2.07 (3H, s), 1.37 (6H, t,J=6.9), 1.14 (3H, t, J=8.1): 781[(M+H)⁺].

[0333] Process 5

[0334] Synthesis of4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0335] 743 mg (1.8 mmol) of the intended product was obtained (yield87%) from 1.6 g (2.0 mmol) of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(2,3,4,6-tetrabenzyl)-β-D-glucopyranosidein the same manner as shown in Process 5 of Example 9.

[0336]¹H-NMR (300 MHz, DMSO-d6) δ: 7.09 (2H, d, J=7.8), 7.03 (2H, d,J=7.8), 5.18 (1H, brd, J=4.5), 5.11 (1H, d, J=6.9), 4.84-5.02 (2H, m),4.26-4.44 (3H, m), 3.40-3.64 (3H, m), 3.04-3.26 (4H, m), 2.51 (2H, q,J=7.5), 2.06 (3H, s), 1.25 (6H, d, J=6.6), 1.14 (3H, t, J=5.7):421[(M+H)⁺], 419[(M−H⁻].

Example 16

[0337] Synthesis of4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-(3-D-glucopyranoside

[0338] 570 mg (1.2 mmol) of the intended product was obtained (yield71%) from 702 mg (1.67 mmol) of4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranosidein the same manner as shown in Example 10.

[0339]¹H-NMR (300 MHz, CDCl₃) δ: 7.08 (4H, s), 4.99 (1H, d, J=7.5),4.24-4.48 (4H, m), 3.77 (3H, s), 3.44-3.68 (6H, m), 2.94-3.16 (2H, m),2.58 (2H, q, J=7.8), 2.09 (3H, s), 1.36 (6H, d, J=6.6), 1.20 (3H, t,J=7.8) ESI-MS(m/z): 479[(M+H)⁺], 477[(M−H)⁻]).

Referential Example 1 Example 35 of WO01/16147

[0340] Synthesis of4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside

[0341] The product was synthesized in accordance with the methodsdescribed in Example 9 (yield point 253 mg).

[0342]¹H-NMR (300 MHz, DMSO-d6): δ: 7.07 (1H, d, J=8.4), 6.75 (1H, d,J=8.4), 5.12-5.20 (2H, m), 5.00 (1H, d, J=3.9), 4.92 (1H, d, J=3.9),4.42-4.56 (2H, m), 3.58-3.68 (1H, m), 3.51 (2H, s), 3.42-3.54 (1H, m),3.06-3.24 (4H, m), 2.00 (3H, s), 1.22 (6H, d, J=6.3) ESI-MS(m/z):409[(M+H)⁺], 407[(M−H)⁻].

[0343] The structures of the compounds shown in Example 1 to 16 andReferential Example 1 are described as follows:

Example 17

[0344] Evaluation of Inhibiting Activity on Renal Brush Border MembraneGlucose Uptake

[0345] The test compound was dissolved in 100 mM Mannitol-10 mMHEPES/Tris (pH 7.4) and solutions having various concentrations wereprepared. Renal brush border membrane was prepared from a rat kidney andthe solutions of the test compounds were added thereto and the productwas incubated at 37° C. for 30 minutes. Then ¹⁴C-D-glucose was added andthe mixture was incubated for 1 minute. After the reaction of glucoseuptake was stopped by a solution containing 1 mM of phloridzin, theactivity of ¹⁴C-D-glucose on ¹⁴C was measured by a liquid scintillationcounter. The intensity of inhibition was calculated by subtracting theamount of taken glucose that is independent on sodium from the amount oftaken glucose of the object samples. The results of the evaluation areshown in Table 1. TABLE 1 Inhibition intensity (concentration The testcompounds of the test compounds) Example Compound 1 84% (10 μM)  ExampleCompound 2 30% (100 μM)

Example 18

[0346] Evaluation of Activity on Rat's Sugar Urine Excretion

[0347] 5-week old male Wistar rats (purchased from Charles River Japan,Inc.) were used in the experiment after they were housed in a metaboliccage for about one week in advance. The test compounds were suspended inolive oil and 20 mg/ml solution was prepared so that the dosage givenper 1 kg of the weight of the rats was 5 ml.

[0348] After the rats were not fed for 4 hours, the test compounds wereorally administered to them at 11 a.m. Their urine was collected, fromthat taken just after the administration to that taken 24 hours afterthe administration and its volume was measured. Then, the concentrationof glucose in urine was measured by glucose oxidase method and urinaryglucose excreted per a day and an individual was calculated. The resultsare shown in Table 2. TABLE 2 The amount of excreted The dosage glucosein urine (mg) Example Compound 4 100 mg/kg 27 Example Compound 6 100mg/kg 59 Example Compound 8 100 mg/kg 4.1 Example Compound 10 100 mg/kg734 Example Compound 14 100 mg/kg 918 Example Compound 16 100 mg/kg 598 30 mg/kg 294  10 mg/kg 263  3 mg/kg 28 Referential Example 100 mg/kg 14Compound 1

[0349] It is obvious from the results shown above that the new pyrazolederivatives have higher inhibiting activity on glucose uptake andactivity on urinary glucose excretion.

[0350] Especially, the inventors have found that the compounds whereinthe substituents of hydroxyl group of glucopyranosyl group are loweralkoxycarbonyl group such as methoxy carbonyl group act as, so-called, aprodrug and the compounds in the present invention have high activity onurinary glucose excretion when they are orally administered.

[0351] The inventors also have found that the compounds wherein any oneof R1, R2, R4, or R5 of general formula (1A) has a fluorine atom haveparticularly high activity on urinary glucose excretion. It is obviousfrom Example 10 and Example 14.

[0352] Further, they have found that the compound of Example 16 hasparticularly high activity on urinary glucose excretion. Examplecompound 16, which has high activity on urinary glucose excretion, stillhas high activity when the compound is orally administered in lowerdoses such as 30 mg/kg or lower. The intended compound is notspecifically described in WO01/16147.

[0353] Besides, Table 2 shows that the compounds of the presentinvention such as example compounds 10, 14 and 16 have much higheractivity on urinary glucose excretion, as compared to Example 35 ofWO01/16147 (Referential Example 1 of the present specification).

[0354] Namely, new pyrazole derivatives of the present invention showoutstanding antidiabetic activity and, therefore, they are highly usefulin the pharmaceutical industry.

What is claimed is;
 1. Pyrazole derivatives of the following general formula (1A) or (1B) or pharmaceutically acceptable salts thereof:

wherein X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated or β-D-glucuronyl group, of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified; Y represents a lower alkyl group or perfluoro lower alkyl group; Z represents a hydrogen atom, lower alkyl group, perfluoro lower alkyl group, aralkyl group or phenyl group; R1 to R5 may be the same or different and represent a hydrogen atom, lower alkyl group, perfluoro lower alkyl group, lower alkoxy group, perfluoro lower alkoxy group, lower alkylthio group, perfluoro lower alkylthio group, lower alkyl amino group, halogeno group, lower alkanoyl group, lower alkenyl group or lower alkynyl group, and n represents an integer from 0 to
 3. 2. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, werein Y in the general formula (1A) or (1B) represents a trifluoromethyl group.
 3. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the general formula (1A) or (1B), Y represents a trifluoromethyl group and n is
 1. 4. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a trifluoromethyl group, n is 1 and X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group.
 5. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a trifluoromethyl group, n is 1 and X is a β-D-glucuronyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group and its carboxyl group may be esterified with lower alkyl group.
 6. The compounds shown below or pharmaceutically acceptable salts thereof among the compounds of claim
 1.


7. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group.
 8. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with lower alkoxycarbonyl group.
 9. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a lower alkyl group having 1 to 3 carbon atoms or perfluoro lower alkyl group having 1 to 6 carbon atoms; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents a hydrogen atom, lower alkyl group, unsubstituted aralkyl group or aralkyl group of which an aryl part at the 4th position is substituted or unsubstituted phenyl group; one of R1, R2, R4 and R5 is a halogeno group, or R1, R2, R4 and R5 are all hydrogen atom and R3 is a lower alkyl group, lower alkoxy group, lower alkenyl group or lower alkynyl group.
 10. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group; R3 is a lower alkyl group and R4 or R5 is a fluorine atom.
 11. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group; R3 is a lower alkoxy group and R4 or R5 is a fluorine atom.
 12. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group and R3 is a lower alkynyl group.
 13. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group; R3 is a lower alkynyl group and R4 or R5 is a fluorine atom.
 14. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group and R3 is a lower alkenyl group.
 15. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents an isopropyl group; R3 is a lower alkenyl group and R4 or R5 is a fluorine atom.
 16. The pyrazole derivatives or pharmaceutically acceptable salts of claim 1, wherein, in the following general formula (1A) or (1B), Y represents a methyl group or trifluoromethyl group; n is 1; X represents a β-D-glucopyranosyl group, of which one or more hydroxyl groups may be acylated with the groups selected from alkanoyl group having 2 to 20 carbon atoms, lower alkoxycarbonyl group and benzoyl group; Z represents a hydrogen atom, isopropyl group, aralkyl group or phenyl group; one of R1, R2, R4 and R5 is a fluorine atom and R3 is a methyl group, ethyl group, methoxy group, vinyl group or ethynyl group.
 17. The pyrazole derivatives of claim 1 selected from the group described below or pharmaceutically acceptable salts thereof. 4-((4-methylthiophenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-O-β-D-glucopyranoside; 4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-1H-pyrazole-3-yl-β-D-glucopyranoside uronic acid; 4-[(4-ethylphenyl)methyl]-1-benzyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside; 4′-[(4′-ethylphenyl)methyl]-1′-benzyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside; 4-[(4-ethylphenyl)methyl]-1-[(4-methoxyphenyl) methyl]-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside; 4′-[(4-ethylphenyl)methyl]-1′-[(4′-methoxyphenyl)methyl]-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside; 4-[(4-ethylphenyl)methyl]-1-phenyl-5-trifluoromethyl-1H-pyrazole-3-O-β-D-glucopyranoside; 4′-[(4′-ethylphenyl)methyl]-1′-phenyl-5′-trifluoromethyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside; 4-[(3-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside; 4′-[(3′-fluoro-4′-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside; 4-[(2-fluoro-4-methoxyphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside; 4′-[(2-fluoro-4-methoxyphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-(6-carbomethoxy)-β-D-glucopyranoside; 4-[(3-fluoro-4-methylphenyl)methyl]-1-isopropyl-5-methyl-1H-pyrazole-3-O-β-D-glucopyranoside; and 4′-[(3′-fluoro-4′-methylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside.
 18. The pyrazole derivatives of claim 1 selected from the group described below or pharmaceutically acceptable salts thereof. 4-[(4-ethylphenyl)methyl]-1-isopropyl-5′-methyl-1H-pyrazole-3-O-β-D-glucopyranoside; and 4′-[(4-ethylphenyl)methyl]-1′-isopropyl-5′-methyl-1H-pyrazole-3′-O-(6-carbomethoxy)-β-D-glucopyranoside.
 19. A pharmaceutical composition comprising the pyrazole derivatives of claim 1 or pharmaceutically acceptable salts thereof
 20. A pharmaceutical composition for the treatment of diabetes which comprises the pyrazole derivatives of claim 1 or pharmaceutically acceptable salts thereof.
 21. A urinary sugar excretion inducer comprising the pyrazole derivatives of claim 1 or pharmaceutically acceptable salts thereof
 22. Use of the pyrazole derivatives of claim 1 or pharmaceutically acceptable salts thereof for producing pharmaceutical compositions which reduce renal glucose reabsorption. 